Cyclodecapentaene compounds

ABSTRACT

Novel 1,6-methano-, 1,6-dichloromethano-, and 1,6difluoromethano- cyclodecapentaene alcohols, aldehydes and acids and derivatives having anti-inflammatory and fibrinolytic activity.

United States Patent [15] 3,683,006 Fried [4 1 Aug. 8, 1972 [54)CYCLODECAPENTAENE COMPOUNDS [58] field of Search ..260/514, 468 [72]Inventor: John H. Fried, Palo Alto, Calif.

[56] References Cited [73] Assigneez Syntex Corporation, Panama,

Panama UNlTED STATES PATENTS [22] Filed: Sept. 9, 1970 3,525,770 8/ 1970Chow ..260/563 [21] Appl' 709% Primary Examiner-Lorraine A. WeinbergerRelated US. Application Data Assistant Examiner-Robert Gerstl [63]Continuation-impart of Ser. No. 742,l40, July Anorney"Evelyn Merker andWalter D reger 3, 1968, abandoned. ABSTRACT U-S. Clo B, 345.9, 347.8,Novel l 6 methano. l 6 dichloromethano and 1 6- 260/4l0, 260/457,260/468 R, 260/ difluoromethanocyclodecapentaene alcohols, al- 260M73260,476 260,479 260/482 dehydes and acids and derivatives havinganti-in- R, 260,484 260/487 260/488 H, flammatory and fibrinolyticactivity.

260/500.5 H [51] Int. Cl. ..C07c 61/28, C070 61/32 11 Claims, NoDrawings yacetate,

1 CYCLODECAPENTAENE COMPOUNDS This is a continuation-in-part of patentapplication Ser. No. 742,140, filed July 3, 1968, now abandoned.

This invention relates to novel cyclodecapentaene compounds of thefollowing fonnulas A and B:

R2 R1 3 R R2 i CZRIi t or. (A) V Q32...

wherein,

\ kyl; and

X is methylene, dichloromethyle'ne or difluoromethylene.

The term lower alkyl in the present context, refers to a straight orbranched saturated acyclic aliphatic hydrocarbon group containingfrom-one to six carbon atoms and l and 2...and 6 and l to 2...to 6carbon atoms;,methyl, ethyLpropyl, butyl, pentyl, and hexyl, the variousisomers thereof. Lower monocyclic alkyl" contains 'three to six carbonatoms, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The termlower alkoxy" refers to the group lower alkyl lower alkyl. being asdefined above. The term lower carboxylic acyloxy refers to a carboxylicacyloxy group containing up to'about eight carbon atoms of a straight,branched .or cyclic chain structure derived from carboxylic anhydridessuch as acetic anhydride,

trifluoroacetic anhydride, propionic anhydride, n-

caproic anhydride, benzoic anhydride, heptoic anhydride, aceticpropionic anhydride, maleic anhydride, phenylacetic anhydride,p-methoxybenzoic anhydride, trimethylacetic anhydride, butyricanhydride, and the like, preferably lower alkanoic anhydrides of up to12' carbon atoms. The expression hydrolyzable esters and ethers, as usedherein, refers to those-physiologically acceptable hydrolyzable estergroups and labile ether 'groups conventionally employed in thepharmaceutical enanthate, caprylate, triethylacetate, pelargonate,decanoate, undecanoate, benzoate, phenylacetate, diphenylacetate,cyclopentylpropionate, methoxaminoacetate, tricliloroacetate,B-chloropropionate, bicyclo [2.2.2] octan-V-carboxylate, adamantoate,dihydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodiumsulfate, sulfate, tetrahydropyran-2'- yl ether, tetrahydrofuran-2'-ylether, 4'-methoxytetrahydropyran-4'-yl ether, and the like.

diethylaminoacetate,'

The compounds of the present invention are prepared by the processoutlined as follows:

With reference to the above reaction sequence, the following definitionsapply: v

R' is hydrogen, lower alkyl, lower monocyclic alkyl, or lower alkoxy;

R 'is hydrogen or lower alkyl;

R is hydrogen, lower alkyl, or lower monocyclic alkyl when takentogether with R and the carbon atom to which R and R are attached;

' R is --CH R or -COOR in which R is hydroxy or a conventionalhydrolyzable ether thereof and R is hydrogen;

R" is lower alkoxy or lower carboxylic acyloxy;

R"'is hydrogen, lower alkyl, or lower monocyclic alkyl; and

each of R, R, R R and X is as defined hereinbefore.

ln one aspect of the process above depicted a 6- lower alkoxynaphthalene compound (1; R lower alkoxy) is reacted with an alkali metaland an alcohol in a lower alkyl amine or diamine or in liquid ammonia toprepare the corresponding 6-lower alkoxy-1,45,8- tetrahydronaphthalene(2; R'=lower alkoxy).

In this reaction, suitable and preferred alkali metals are sodium,potassium and lithium. This reaction is conveniently conducted in thepresence of a monohydric lower alkanol of from one to six carbon atomssuch as methanol, ethanol n-propanol, isopropanol, n-butanol,isobutanol, sec-butanol, t-butanol, n-amyl alcohol, and the like, eitheralone or in admixture with other organic liquid reaction media, such asdioxane, tetrahydrofuran, diethyl ether, glyme,

dimethyl-sulfoxide, n-hexane, and the like. The reaction is furtherconducted at temperatures ranging from about 80 to 100C. and for aperiod of time sufiicient to produce product, ranging from about fiveminutes to about two weeks.

The compound (2) is then treated with acid, for example, oxalic acid,acetic acid, and the like to obtain the corresponding 6-oxo-l ,4,5,6,7,8-hexahydronaphthalene(3). This compound is then reduced such aswith sodium borohydride to form the corresponding 6-hydroxy compound(4). To the 6-hydroxyl ,4,5,6,7,S-hexahydronaphthalene (3) is added thegroup wherein each X is hydrogen, chloro, fluoro, across the C-9,ldouble bond to yield the corresponding 6- hydroxy-9, l0-bridgedl ,4,5,6,7,8,9, l O-octahydronaphthalene (5). The resultant compound (5) isoxidized to the 6-oxo compound (6) such as with chromic acid inpyridine. The 6-oxo-9,l0-bridgedl ,4,5,7,8,9,lO-heptahydronaphthalene(6) is converted to the corresponding enol ethers and enol acetates (7)via conventional methods known per se. In this method, each of or bothof the 9,10-bridgedl,4,5,8,9.l0-hexahydro-6-enol product and 9,10-bridged-l ,4,7,8,9, l 0-hexahydro-6-enol product may be formed dependingupon the conditions employed. They are separable by conventionaltechniques and each or the mixture is useful for preparing compounds(8). The resultant compounds (7) are then treated with a benzoquinone toyield the corresponding 6-lower alkoxyand -lower carboxylicacyloxy-l,6-bridged-[ l0]- annulenes (8; R=lower alkoxy or lowercarboxylic acyloxy).

In the OX2 group addition, the

group is generally generated in situ and in the presence of inert,liquid organic reaction medium. Suitablemedia include those definedinfra for the benzoquinone reagent aa well as the chlorinatedhydrocarbon solvents such as methylene chloride, chloroform and carbontetrachloride.

The halocarbene reactant is generated from a haloforrn and alkali metaltertiary alkoxide, or from an alkali or alkaline earth metal salt of atrihaloacetic acid such as sodium trichloroacetate, or from aphenyltrihalomethyl mercury such as phenyltrifluoromethyl mercury andphenyltrichloromethyl mercury.

The halocarbene reactant is prepared by reacting together a haloforrn,wherein the halo is defined above,

with an alkali alkoxide, preferably an alkali metal tertiary alkoxide.In one procedure, the reaction mixture containing haloform and alkalimetal tertiary alkoxide is heated to the boiling point and maintainedunder reflux for a period of time sufficient to produce the halocarbenereactant ranging from about 30 minutes to about 5 hours. Suitablehaloforrns employed in the above process include chloroform,

bromodichloromethane, and chlorodifluoromethane.

Representative alkali metal tertiary alkoxides employed in the aboveprocess include potassium t-butoxide and sodium t-amylate.

The reaction can also be performed by reacting together the startingcompound and a phenyltrihalomethyl mercury such as phenyltrifluoromethylmercury and phenyltrichloromethyl mercury. This reaction is convenientlyconducted in liquid organic reaction medium, such as those listed above,and at temperatures of from about 25C. to the boiling point of thereaction mixture.

In another procedure, the starting compound is reacted with an alkali oralkaline earth metal salt of a trihaloacetic acid in an organic solvent,preferably diglyme or triglyme, and at a temperature above thedecomposition temperature of the salt. In this regard, the details ofU.S. Pat. No. 3,338,928 are hereby incorporated by reference.

In those instances in which each X is hydrogen, the methylene group isgenerated from zinczcopper couple, methylene iodide reagent. Thezinczcopper couple methylene iodide reagent is prepared from zinc dust,a copper salt such as cuprous chloride and methylene and methyleneiodide. Typically, the reagent is prepared by contacting together amixture of the copper salt, zinc dust, and an organic solvent, such asdiethyl ether, and methylene iodide, conveniently at the refluxtemperature of the mixture. See U.S. Patent 3,408,372, which is herebyincorporated by reference.

The last step; (7 8) involves reaction with a benzo-quinone. Thisreaction is conveniently performed in the presence of inert, liquidorganic reaction medium. Suitable media include the normally employedorganic solvents such as tetrahydrofuran, dioxane, dimethylformamide,n-hexane, toluene, benzene, mesitylene, diethyl ether, the monoordi-lower alkyl ethers of diethylene glycol or triethylene glycol, forexample, diglyme and triglyme, and the like. This reaction is furtherconducted at temperatures ranging from about 0C. up to the boiling pointof the reaction mixture and under reflux for a period of time sufficientto complete the reaction ranging from about a few minutes to about 48hours.

The reaction may be performed in the presence of an anhydrous acid suchas p-toluene sulfonic acid, hydrochloric, perchloric and sulfuric;however, the use of these acids is not necessary in the preferredembodiments hereof.

Suitable benzoquinones for this reaction include the ortho andparabenzoquinones which can be unsubstituted or substituted with one ormore groups, notably acyl and cyano and halogen, including in the lattercategory, bromo, chloro, and fluoro Typical benzoquinones include1,2-benzoquinone, 1,4- benzoquinone, 2,3-dichloro-5,-dicyano-l ,4-benzoquinone, tetrachloro-1,2-benzoquinone, 2,3- difluoro-l,4-benzoquinone, 2,3-dibenzoyl-l ,4-

benzoquinone, 2,3-dicyano-l,4-benzoquinone, tetrachloro-1,4-benzoquinone, 2,3-difluorol ,2- benzoquinone,2,3-dicyano-l,2-benzoquinone, and the like. Preferred is2,3-dichloro-5,6-dicyano-l,4- benzoquinone (DDQ). 1

in carrying out this reaction, the starting Compound (7) and thebenzoquinone are mixed and maintained together in any convenient orderor fashion. The reaction mixture is then maintained within the giventemperature range for a period of time sufficient to complete thereaction. Upon the completion of the reaction, the reaction mixture isprocessed by conventional procedures such as dilution, chromatography,decantation, filtration, distillation, evaporation, andso forth torecover and isolate the desired product.

The given reaction consumes the respective reactants in the ratio of onemole of the starting compound (formula 7) per two moles of thebenzoquinone reactant. Thus, while the use of chemical equivalentamounts of the reactants is preferred; it is not an absolute necessity,some of the desired product being prepared when employing anyproportions hereof. In the usual practice, amounts of the benzoquinoneare employed which range from about two moles to about 50 moles,preferably from about 2 to about 5 moles, per mole of starting compound.

In those instances wherein each X in the starting material is chloro,the l,6-dichloromethano-2,5- dihydro-[l01-annulene intermediate compoundis prepared. This is readily converted to the 1,6- dichloromethano-[l0]-annulene product by first converting it to the corresponding3,4-dibrorno compound followed by the dehydrobromination thereof.

In those instances in which each X in the starting material (7) isfluoro, the employment-of about one mole of the benzoquinone resultspredominantly in the preparation of l,6-difluoromethano-2,5-dihydro-[l0}- annulene. When employing amounts of benzoquinone in excess of abouttwo moles per mole of starting material (7), thel,6-difluoro-methano-[l0]-annulene is produced.

With reference again to the above reaction sequence l to the6-unsubstituted (R hydrogen) or 6-substituted (wherein R lower alkyl orlower monocyclic alkyl) naphthylene (l) is converted to thecorresponding l,4,5,8-tetrahydro-naphthylene compounds (2) as set forthabove. To this compound is then added the substituted compounds of thepresent invention represented above by formulas (A) and (B). Thesubstituent R in formulas (8) and (I0) varies as the method ofpreparation from the compounds of formu- [as (7) and (9). The a-carbonatom alkyl groups (R,

R alkyl) and the a-carbon atom spiro groups (R and R with attachedcarbon atom monocyclic alkyl) can be present on the starting compound(1) (R and R definitions) or they can be introduced into compounds (8).In either event, the alkyl groups are introduced by alkylation of alower alkyl ester of an acid of formulas l or 8) followed by hydrolysisof the ester to the free acid. In the formation of the monoalkylcompounds, i.e one of R" (R and R (R is hydrogen; one equivalent amountof alkylating agent is employed. Dialkyl compounds are prepared with atleast two equivalents of alkylating agent where the alkyl groups are thesame or consecutively with one equivalent each where the alkyl groupsare different. The alkylation can be carried out by treating an alkylester of the acid with alkylating agent comprising an alkali metalhydride such as sodium hydride and a lower alkyl iodide in an organicsolvent such as the ethers, e.g.l,2dimethoxyethane, and thereafterremoving the ester group by treatment with base, e.g., an alkali metalhydroxide or carbonate, in a lower alcohol such as methanol to affordthe corresponding free acid.

The compounds of the present invention having a spiro lower monocyclicalkyl group in combination with the a-carbon atom are prepared bytreating a lower alkyl ester of an acid of formula (8) or (1) wherein R=R =hydrogen with an a,w-dibromoalkane, such as 1,3-dibromopropane,1,4-dibromo-butane, and l,5-dibromopentane, and sodium hydride in anorganic solvent such as glyme. The a-spiro cyclopropyl group'isintroduced by treating the a-exo methylene with methylene iodide andzinczcopper couple in accordance with Simmons-Smith conditions which areknown per se.

The compounds of the present invention having an a-carbon exo methylenegroup(R and R together are methylene) are prepared by treating a loweralkyl ester of an acid of formula ('8) with formaldehyde orparaformaldehyde and an alkali metal alkoxide in dimethylsulfoxide.Thereafter, the a-methylene ester can be hydrolyzed to the correspondingacid.

The elaborative groups represented by R in formula (10) are introducedusing the compounds of formula (8). Alkali metal salts of the acids (8)can be prepared by treatment with a molar equivalent of an alkali metalbicarbonate, or the like, such a sodium bicarbonate, or potassiumbicarbonate or by titrating a solution of the acid (8) with an alcoholsolution of the appropriate alkali metal alkoxide such as sodiummethoxide, potassium methoxide, and the like.

Lower alkyl esters of the acids (8) can be obtained directly by treatingthe acid with ethereal diazoalkane such as diazomethane or diazoethaneor by treating the alkali metal salts of the acids (8) with a loweralkyl iodide or bromide such as methyl iodide, ethyl iodide, and thelike, in an organic solvent such as dimethylacetamide ordimethylformamide.

The acids or esters can be reduced using, e.g. lithium aluminum hydridein tetrahydrofuran, to afford the corresponding alcohol (10; R =CH OH)which can be oxidized such as with chromic acid in pyridine or Moffattconditions or with silver oxide to afford the aldehyde (10; R"=CI-IO).

Compounds of the present invention of formulas (10) wherein R is CH -Rin which R is hydroxy can be esterified and etherified to obtain thecortrimethylamine complex in pyridine or by procedures such as describedby Komel et al., Steroids 4, (1964); Kirdani, Steroids 6, (1965) andBernstein, Steroids 7, 577 1966). Phosphate esters can be prepared fromthe free hydroxy compounds by treatment with, e.g. B-cyanoethylphosphate in the presence of N,N- dicyclohexylcarbodiimide inpyridine or by the method ment with anhydrous ammonia or lower alkyl ordiloweralkyl amine. By treating an acid of formulas A and B withhydroxylamine hydrochloride in the presence of sodium methoxide, thenovel hydroxamic acids of Formula (10) (R is -CONHOl-l) are obtained. 7

Alternatively, the novel compounds of the present invention of formula(A) above wherein R is R can be prepared using the following outlinedprocedure wherein Ac is an acyl group, e.g. a lower carboxylic acyl suchas acetyl, R is an acid labile protecting group such astetrahydropyran-Z-yloxy, tetrahydrofuran-2- yloxy, t-butyloxy and thelike, X is dichloromethylene or difluoromethylene and X is as definedabove.

(III) of Wendler, Chem. 86 lnd., i174 (1967) or US. Pats. Nos.2,936,313, 3,248,408, or 3,254,100. Alkali metal salts of the esters canbe made to treatment with base, e.g. sodium ethylate, sodium orpotassium bicarbonate, and the like. By controlling the amount of base,both the mono and di salts can be obtained.

By treatment of a free alcohol of formula (l) with dihydropyran ordihydrofuran in the presence of an acid catalyst, tetrahydropyranyl andtetrahydrofuranyl ethers are obtained. Tetrahydropyranyl ethers andtetrahydrofuranyl ethers can also be prepared by reacting the freealcohol with about a molar equivalent of 2- benzoyloxytetrahydropyranand 2-benzoyloxytetrahydrofuran, respectively, in an inert organicsolvent under substantially neutral conditions. The 4-methoxytetrahydropyran-4-yl ethers are obtained by reacting the freealcohol with an excess of 4-methoxy- 5,6-dihydro-2l-l-pyran in thepresence of a small amount of an acidic catalyst such asp-toluenesulfonic acid at about room temperature.

Acid amides of formulas (R is +CON(R are prepared, for example, bytreating an acid of formulas A and B with thionyl chloride followed bytreat- In carrying out the procedures outlined above, 2- naphthylaceticacid (I) is reduced to l,4,5,8- tetrahydro-Z-naphthylacetic acid (II) bytreatment with an alkali metal such as sodium, potassium or lithium inliquid ammonia in the presence of a lower alcohol such as ethanol,t-butanol, and the like. The acid (ll) is treated with a reducing agentsuch as lithium aluminum hydride to afford 2-(l',4',5,8'2-

naphthyl)ethanol (Ill). The conversion of (ll) to (Hi) can also becarried out by first preparing the corresponding alkyl ester of (ll),e.g. by treating (II) with diazamethane in ether to obtain the methylester of (ll), and then reacting the alkyl ester of (ll) with lithiumaluminum hydride to obtain the alcohol (Ill). The alcohol (III) is nextesterified in a conventional manner, e.g., by treatment with acarboxylic anhydride such as acetic anhydride in pyridine, to obtain thecarboxylic ester (IV) which is reacted with a dichlorocarbene ordifluorocarbene generated from sodium trichloroacetate and sodiumchlorodifluoroacetate, respectively, to furnish the acetate of 2-(9',l0-dichloromethylene-l ,4 ,5 ,8,9',10-hexahydro-2- naphthyl)ethanol (V; X'is CCl and Ac is acetyl) and which is etherified using, e.g.dihydropyran or 10 dihydrofuran ina hydrocarbon solvent in the presenceThe alkali metal salts and lower alkyl esters of the acids (XI) areprepared as discussed above. Similarly, the a-carbon alkyl, spiro alkyl,and exo methylene groups are introduced on the acids (XI) as describedabove.

As an alternative, the compounds of the present invention of formula (A)above wherein R is lower alkoxy or lower carboxylic acyloxy are preparedaccording to the following outlined procedure.

of an acid catalyst such as p-toluenesulfonic acid and then brominatingusing bromine in aninert organic solvent such as chloroform, carbontetrachloride, or the like, to afford the tetrahydropyran-Z-yI ether ortetrahydrofuran-Z-yl ether of 2-(2,3,6',7' o 'mefi b e hxslr i'1anaphthyl)ethanol (VII). The tetrabromo compound (VI) upon treatment withbase such as an alkali metal hydroxide or alkali metal alkoxide e.g.sodium hydroxide, sodium methoxide, potassium t-butoxide and sodiumt-butoxide, in an organic solvent such as ether, ethanol, diglyme,dioxane, hexamethylphosphoramide, dimethyl sulfoxide, tetrahydrofuran,and the like, is converted into the tetrahydropyran-Z-yl ether ortetrahydrofuran-Z-yl ether of2'(l,6-methanocyclodecapentaen-3-yl)-ethanol (VIII) which is hydrolyzedby treatment with acid to furnish the corresponding free alcohol (IX; Xis CH The alcohol (IX) is oxidized using chromium trioxide in pyridine,Jones reagent or the procedure of U.S. Pat. No. 3,248, 380 to afford thecorresponding aldehyde (X) which upon further oxidation is convertedinto the acid (XI).

A tetrabromo compound of formula (V) is obtained by treating a compoundof formula (V) with bromine in an inert organic solvent as describedabove. The 9', ldichlorornethylene-Z' ,3 ,6 ,7 '-tetrabromo or 9' 10'-difluoromethylene-Z',3',6',7-tetrabromo compound (V) is then treatedwith base as previously described to afford the alcohol (IX) wherein Xis dichloromethano or difluoromethano, respectively. The correspondingaldehydes and acids of formulas I (X) and (XI) are obtained by oxidationof the (IX) wherein X is dichloromethano or difluoromethano,respectively. The corresponding aldehydes and acids of formulas (X) and(XI) are obtained by oxidation of the (XIX) (XVIII) In the aboveformulas Ac, R, X, and X are as defined above. In the practice of theabove process, 2 6-methoxyl ,4 ,5 ,8-tetrahydro-2- naphthyl)ethanol(XII) (prepared by reducing 6 methoxyQ-naphthylacetic acid or2-(6-methoxy-2'- naphthyl)ethanol using the method described above) istreated with acid, e.g. oxalic acid, acetic acid, or the like, to obtain2-(6'-oxo-l ',4',5,6',7',8-hexahydro-2- naphthyD-ethanol (XIII) whichafter reduction of 6- 0x0 to -hydroxy as described above, is treatedwith sodium trichloroacetate or sodium 'chlorodifluoroacetate followedby oxidation to afford 9',10-octahydro-2-naphthyl)ethanol and 2 -(6-0xo-9 ,1()Fdifluoromethylene-l,4,5,6,7,8,9',10-octahydro-2-naphthyl ethanol,respectively, followed by etherification with dihydropyran ordihydrofuran to furnish the corresponding tetrahydropyran-2"-yl esterand tetrahydrofuran-2-yl ester, respectively, of formula (XIV). A9',l0'-dichloromethylene of formula (XIV) is then converted into the6-hydroxy-9,l0'- methylene derivative (XV) using an alkali metal inliquid ammonia which is oxidized using, e.g. chromium trioxide inpyridine to afford the ether of 2(6'-oxo-9,l0-methylene-1,4',5',6,7',8,9,l0-octahydro-2- naphthyl) ethanol (XVI).Compounds of formulas (XVI) or (XIV) are next converted into thecorresponding 7,8-dehydro compounds (XVIII). This conversion can becarried out directly using 2,3-dichloro- 5,6-dicyano-l ,4-benzoquinonein dioxane under reflux, selenium dioxide, and the like, or by firstforming the 7-bromo intermediate (XVII) by treatment with cupric bromidein a lower alcohol such as methanol and then dehydrobrominating bytreatment with an alkali halide and an alkali metal carbonate orbicarbonate or alkaline earth salt such as lithium bromide and sodiumbicarbonate, lithium chloride, and sodium carbonate lithium bromide, andcalcium carbonate, and the like, The tetrahydropyran-2"-yl ether ortetrahydrofuran-2"-yl or t-butyl ether of a 2-(6'-oxo-9,10- methylene-,-dichloromethylene-, or difluoromethylene-l ',4'5 ,6',9, l'-hexahydro-2'- naphthyl)-ethanol(XVIII) is treated with a carboxylicanhydride such as acetic anhydride, propionic anhydride, butyricanhydride, and the like, and an alkali metal acetate such as sodiumacetate to obtain the ether of 2'(8'-acyloxy-l ',6'-methano-,dichloromethano-, or -difluoromethanocyclodecatetraen-3'-yl)ethanol(XIX), e.g. the

tetrahydropyran-2"-yl or t-butyl ether of 2-(8'-acetoxyl',6-methano-cyclodecatetraen-3 '-yl)ethanol (X- IX). Ac is acetyl, X isCH R is tetrahydropyran-2"- yloxy or t-butyloxy) is prepared from thetetrahydropyran-2"-yl or t-butyl ether of 2-(6-'-oxo- 9',lO'A-methylenel ,4',5,6 ,9, l 0-hexahydro-2'- naphthyl)ethanol (XVII); Xis CI-I R is tetrahydropyran-2"-yloxy or t-butyloxy). A

cyclodecatetraene of formula (XIX) is converted into the correspondingcyclodecapentaene (XX) using N- bromosuccinimide in carbontetrachloride, palladium catalyst, 2,3-dichloro- ,G-dicyanol,4-benzoquinone, and the like. An ether of formula (XX), e.g. thetetrahydropyran-2"-yl or t-butyl ether of 2-(8'-acetoxyl ,6-methanocyclodecapentaen-3 '-yl)ethanol (XX); Ac is acetyl, X is CH R istetrahydropyran-2"-yloxy or t-butyloxy), is then hydrolyzed by treatmentwith acid to furnish the corresponding free alcohol which can beoxidized using one of the methods described hereinabove to furnish thealdehyde and acids.

The compounds of formula (A) wherein R is lower alkoxy are obtained fromcompounds of fonnula (XX) by treatment with base, e.g. an alkali metalbicarbonate such as potassium bicarbonate in aqueous methanol, followedby treatment with a lower alkyl orthoester such as a lower alkylorthoformate, e.g. methyl orthofonnate, ethyl orthoformate, n-propylorthoformate, and the like, in the presence of an acid catalyst such asp-toluenesulfonic acid. By this method, the compounds of formula (XX)can be converted into the compounds of formula (XXI) which can beoxidized using one of the above methods to obtain the correspondingaldehydes and acids. In the following formula, X is as definedhereinabove and alkyl is lower alkyl.

cm-om-on l X Alkyl o (XXI) The above compounds (XXI) also can beconverted into the corresponding mono or dialkyl substituted derivativesusing the alkylation procedures described substituted naphthalenecompounds, e.g. lnaphthylacetic acid and 6-methoxy-l-naphthylacetic acidin place of 2-naphthylacetic acid and 6-methoxy- 2-naphthylacetic acid,respectively.

The starting compounds of formulas (l) and (I) can be prepared from2-tetralone by treating the latter with an equivalent of an alkyl orcycloalkyl magnesium bromide in an ether to obtain the corresponding2-alkyland 2-cycloalkyl-3,4-dihydronaphthalene which is dehydrogenatedby heating with palladium charcoal catalyst to afford the corresponding2-alkylor 2- cycloalkyl-naphthalene. The resultant Z-substitutednaphthalenes (including 2-lowera1koxy naphthalenes) are then reactedwith acetyl chloride in nitrobenzene in the presence of at least threemolar equivalents of aluminum chloride to afford the corresponding6-substituted-Z-acetylnaphthalene. The resulting compound is heated withmorpholine, in the presence of sulfur at about C, the resultant compoundis refluxed with concentrated hydrochloric acid to furnish thecorresponding 2 (6-substituted-2'-naphthyl)-acetic acid compound.

The addition of an alkyl substituent at the Ga position is carried outby esterifying the 2-(6-substituted- 2-naphthyl)-acetic acid derivativeby conventional methods; such as by treatment with a diazoalkane, suchas diazomethane, in ether to afford the corresponding alkyl ester. Theester product is then treated with sodium hydride in an ether solvent,such as l,2-dimethoxyethane; and then treated with an alkyl halide, suchas methyl iodide, to afford the corresponding2-(6'-substituted-2'-naphthyl)propionic acid alkyl ester.

In like manner, as described above, the compounds containing an alphacarbon exo methylene group or a lower monocyclic alkyl group incombination with the alpha carbon in the R lower alkoxy or lowercarboxylic acyloxy series are prepared in accordance with the proceduresdescribed above for the R hydrogen compounds.

The starting compounds of formulas (l) and (I) in the C-1 series areformed by first preparing the 2-substituted naphthalenes as set forthabove. The substituted naphthalenes are reduced with two molarequivalents of hydrogen in the presence of a platinum, palladium, nickelcatalyst,or the like, to afford the corresponding substituted tetralin(hydrogenation of the unsubstituted ring is favored; when both rings aresubstituted, two products are obtained with different ring saturation).The substituted tetralin is then oxidized, such as with chromiumtrioxide in glacial acetic acid or 8N sulfuric acid, to obtain the6-substituted ltetralone.

The reaction of the l-tetralones with one or more equivalents of al-carboalkoxyalkylidene triphenyl phosphorane, such asl-carbomethoxyethylidene triphenyl phosphorane, to furnish thecorresponding 1- carboalkoxyalkylidene)-tetralin. The latter uponheating with palladium charcoal catalyst affords the correspondingl-naphthylacetic acid ester derivative.

For this purpose, the l-carboalkoxyalkylidene triphenyl phosphoranereactant is conveniently provided upon reaction of triphenylphosphinewith a 2- halocarboxylic acid ester in an organic reaction mediumfollowed by reaction with a base.

four to six carbon atoms and those wherein R and R l3. 14 Thus, forexample, by reacting 6-methoxy-l- EXAMPLEI tetralone with atriphenylphosphorane derived from ethyl LhaloProPionate, IHlcarboethoxyeth li,li To a mixture of 1.6 g. of B-methoxynaphthalene, 1.6

f acetyl chloride, and 20 ml. of nitrobenzene, 4.0 g.yhdene)-6-methoxytetralm is prepared. Dehydrogenag o tion thereofprovides ethyl 6 methoxy 1 naphthyl a 5 of aluminum chloride are slowlyadded. The resulting mixture is stirred for 48 hours at 25C.; then it is22:2 iti s yfi l l' ggg g gggi affords 6- washed with water until freeof chloride. The mixture is The compounds of the present inventionexhibit dried over sodium sulfate and evaporated under geometricalisomerism due to chirality of the bridehead reduced pressilre' The 'l inannulene ring system. In addition, those compounds ynaphthalene refluxedm 2 ml of morpholme P having an asymmetric carbon atom those whereintaining one-half gram of sulfur for 2 hours; the reaction R and R aredifferent and not botli hydrogen are optimixture f q and evaporatla'd'Ijhe resulting cally active. Each of the isomers resulting either fromthlo amlde derwanve. ls extracted wlth methyl elher; asymmetriccarbonatoms and/or chimfity mixtures the extracts are combined and evaporated.The residue thereof axe indicated within the scope hereof These isrefluxed in 10 ml. of concentrated hydrochloric acid o isomers can beseparated by conventional means such for i f E s k gz i as by formingsalts of the acids with active amines such aqueous mm y mm e mm l d easbrucine, cinchonine, methylamine, morphine, quin- "acted l l theextracts l q The idine, quinine, strychnine, or the like, and thereafteraqueous layer acldlfied and the preclpltated 6' methoxy-2-naphthylaceticacid filtered. separating the dlasteriomenc salts by fractionalcrystallization followed by regeneration of the free acid. S'mllafly6'methyl'2'naphthylaceuc acld 6 ethyl 2 The compounds of the presentinvention of formulas naphthylacefic acid 'ethoiiyanappmylacefic acid 6-(A) and (B) wherein one of R is hydrogen and the cyclprpyl'2'nap!1mylaceuc acid f i other is alkyl of one to three carbon atoms andthose naphthylaceuc f f wherein R and R together are methylene are Rtherapeutically useful anti-inflammatory agents, anal- P fl6'cyclobutym'naphthylacem gesic agents, and anti-pyretic agents. Thus,they are acldr 6'cyclohexy"z'naphthylacefic acid, 'P PY Y' useful forthe treatment of inflammatory conditions of znaphthylacetic acid,6'hexyl'z'naphthylacetic acid the skin, bones and muscles and painassociated -p y -2- p y e i acid, 0propyloxy-2- therewith such ascontact dermatitis, bursitis, arthritis, nap hy ceti c and p y c a a epruritus, and the like. They can be administered and prepared from theirrespective corresponding used in the same way as phenylbutazone. Forexample, naphthalene starting materials. they can be administered orallyto animals such as cats, dogs, horses, and the like for the treatment ofpainful EXAMPLE 2 arthritic and skeletal muscular disorders; To amixture f 22 f methyl 2 2'- The fi of formulas (A) and naphthyl)-acetate(prepared by treating 20.5 g. of 2-(6' one of R and R IS hydrogen andthe other IS alkyl of methxy 2, naphthyl) aceflc acid with 45 of 40diazomethane in ether), and 2.5 g. of sodium hydride in bon atom towhich R and Ris attached are lower i g t z l ifi fgi ggxfixza iifibf2:32: g i monocyclic alkyl are (l) hypocholesteroemic agents e e an rand 2 fibrinolytic agents. They arethus useful for 1 I z j l s s I: f g?g; lowering serum cholesterol levels and(2) the treatment an v "h i h Cr e of thromboembolic conditions by lysing preformed ex rac are com mewas e wit water to neutra rty, fibrin. They can be administered and usedin the same 2' sodum Sulfate and filtered and evaporated way as agentspossessing like activity such as (l) varito Yleld methyl y' p y oussterols and (2) actase or thrombolysin. p p f The following examples areprovided to illustrate the Thls f l P hydrolyzed to practice of thepresent invention. In the present specifirespondlng dslmllarly, the h rl ed cation and claims, the term bridged refers to a products of Example1 are converted to the cormethano or dihalomethano group of the formularesponding propionic acid and esters.

\CXI EXAMPLE 3 are each alkyl and those wherein R and R and the car- Toa solution of one chemical equivalent of tripheneach Xbeing as definedabove. In the present specificaylpliosphme m 30 of benzene ls onechemulal tion and claims, the root term lol-annulene and the cof ethyl2'bmmo'9pmpl0nat? and he root. term .tcyclodecapemaene" may be used 6ture IS refluxed for 1 hour. The reaction mixture is terchangeably torefer to the following basi l thereafter filtered and the insolublematerial recovered and added to 50 ml. of tetrahydrofuran. Oneequivalent of sodium methoxide is added and the mixture is stirred untila solution forms.

To the thus prepared Wittig reagent is added one chemical equivalent of6-methoxy-l-tetralone and the resultant mixture is heated attemperatures in the range of 150 to 200C. until complete reaction isindicated by means of a chromatoplate. The cool reaction mixture istriturated with hexane and the crystalline triphenylphosphine oxideremoved by filtration. The filtrate which contains6-methoxy-l,1-(1'-carbethoxyeth-1,l '-ylidene)tetralone is concentratedin vacuum and the residue heated with percent palladiumoncharcoalcatalyst 100 mg. per gram of ester) at 180C. for 5 hours giving ethyl6-methoxy-l-naphthyl-amethylacetate.

A suspension of l g. of ethyl 6-methoxyl -naphthyl-a -methylacetate in60 ml. of methanol is treated with a solution of 1 g. of potassiumcarbonate in 6 ml. of water. The mixture is heated at reflux for 1 hour,cooled in ice and diluted with water. The solid which forms is collectedby filtration, washed with water, and dried to yield6-methoxy-l-naphthyl-a-methylacetic acid which is recrystallized fromacetonezhexane.

Similarly, the 6-substituted l-naphthyl acid compounds otherwisecorresponding to those of Example 1 are prepared by practicing the aboveprocedures.

EXAMPLE 4 Liquid ammonia which has been dried over sodium metal anddistilled (600 ml.), 300 ml. of dry tetrahydrofuran, and 150 ml. of drymethanol are mixed together with stirring. After the mixing period,grams of Z-naphthylacetic acid are added to the mixture while continuingstirring. To the resultant mixture are added 5 grams of lithium wire in0.5 gram portions over a period of 2 hours while maintaining thereaction mixture at reflux temperature. After the end of the reactionperiod, the ammonia is allowed to evaporate and water (100 ml.) and then10 percent hydrochloric acid (200 ml.) are added. The reaction mixtureis then extracted with ethyl acetate and the extracts dried over sodiumsulfate and evaporated. The residue after evaporation is recrystallizedfrom methanol to provide (1',4',5',8-tetrahydronaphth-2'- yl)-aceticacid.

In accordance with the foregoing procedure, the corresponding l',4',5,8-tetrahydronaphth-1'-yl)-acetic acid is prepared as well as thecorresponding 6-substituted derivatives thereof from the startingcompounds of Examples 1,2, and 3.

EXAMPLE 5 A solution of 10 g. of 6-methoxynaphth-2-ylacetic acid in 500ml. of methanol is treated with 10 ml. of methanol which is saturatedwith hydrochloric acid gas. After maintaining this treatment for 6 hoursat C., the solution is evaporated providing methyl 6-methoxynaphth-Z-ylacetate.

A solution of l g. of methyl 6-methoxynaphth-2-yl acetate in 50 ml. oftetrahydrofuran is added, over a-30 minute period, to a stirredsuspension of l g. of lithium aluminum hydride in 50 ml. of anhydroustetrahydrofuran. The mixture is heated at reflux for 2 hours. To themixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water.Sodium sulfate is next added, the mixture is filtered and the solid thuscollected is washed with hot ethyl acetate. The combined organicsolutions are then evaporated to yield 2-(6'-methoxynaphth-2-yl)-ethanol which may be further purified through recrystallization fromacetonezhexane.

The thus prepared compound is treated according to the procedure ofExample 4 to provide 2-(6-methoxy- 1,4 ,5 ,8-tetrahydro-2-yl)-ethanol.

EXAMPLE 6 To a mixture of 2 g. of 2-(6'-methoxy-1',4',5,8'-tetra-hydronaphth-2'-yl)-ethanol and 35 ml. of methanol is added asolution of oxalic acid (0.1 g.) in water (5 ml.). This mixture is leftat room temperature for about 2 hours and is then diluted with water andextracted with methylene chloride. The methylene chloride extracts arecombined and then washed, dried and evaporated to give2-(6'-oxo-1',4',5',6',7',8'-hexahydronaphth-Z'-yl)-ethanol.

EXAMPLE 7 A solution of l g. of2-(6'-oxo-1',4,5,6,7',8'hexahydronaphth-2-yl)ethanol in ml. oftetrahydrofuran is added over a 30 minute period to a stirred suspensionof 1 g. of lithium aluminum hydride in 50 ml. of anhydroustetrahydrofuran and this mixture is heated at reflux for 2 hours. To themixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water.Sodium sulfate is next added, the mixture is filtered and the solid thuscollected is washed with hot ethyl acetate. The combined organicsolutions are then evaporated to yield2-(6'-hydroxy-1',4',5',6',7',8'-hexahydronaphth-2'-yl)ethanol which maybe further purified through recrystallization from acetonezhexane.

EXAMPLE 8 Zinc dust (2.65 grams) and 0.75 grams of cuprous chloride aredispersed in 12.5 ml. of diethyl ether and ice water. The resultantmixture is maintained at 0C.

yl )-ethano1 product.

' EXAMPLE9 Part A 2-(6-hydroxy-1',4',5',6',7',8'-hexahydronaphth-2'-yl)-propionic acid methyl ester (prepared as set forth in Examples 5 to7) (40 grams) and 42.5 grams of potassium t-butoxide are added to 2liters of ether at 5 5C. with stirring. To the resultant mixture isadded 36 grams of chloroform in 200 ml. of ether. The resultant reactionmixture is allowed to attain room temperature and then filtered andevaporated. The residue is recrystallized from ether: hexane to providethe 2-(6'- hydroxy-9 .10 -dichloromethano-l ',4' ,5 ,6 ,7 ,8 ,9

lQL-octahydronaphth-ZGyllpropionic acid methylester product.

PartB i To a stirred and refluxing solution of l g. of 2-( 6- hydroxy-(l ',4',5',6',7',8'-hexahydronaphth-2'-yl)- propionic acid methyl esterin ml. of dimethyl triethylene glycol ether is added in a dropwisefashion and under nitrogen, 10 ml. of a50 percent w/v solution of sodiumtrichloroacetate. The solution is cooled and filtered and the filtrateis evaporated to dryness under reduced pressure. The residue thusobtained is chromatographed on alumina, eluting with hexanenitrogen.There is then added one additional gram of ester product;

EXAMPLE 10 (6'-l-lydroxy-l ,4 ,5 ,6 ,7' ,8 '-hexahydronaphth-2'-yl)acetic acid (4 grams) and 2.5 grams of potassium tbutoxide aredispersed in 200 mls. of diethylether at -5 5C. Five grams ofchlorodifluoromethane in 50 ml. of ether are then added and the mixtureis allowed to warm to room temperature. The solution is then filteredand evaporated and the residue recrystallized from ethyl acetate at C.to provide the (6'-hydroxy-9', l 0'-difluoromethanol ',4',5',6,7',8',9',l0-octahydronaphth-2'-yl)acetic acid product.

The procedures of Parts B and C of Example 9 are repeated using thestarting material of the first paragraph of this example and sodiumchlorodifluoroacetate and phenyltrifluoromethyl mercury, respectively,to provide the (6-hydroxy-9',lO'- difluoromethano-l ',4',5',6',7',8',9',l 0'-octahydronaphth-2'-yl)acetic acid product.

EXAMPLE 1 l A solution of 6 g. of 2-(6'-hydroxy-9',l0'-methanol',4' ,6,7 ,8 ,9 ,1 0' -octahydronaphth-Z' -yD-acetic acid in 120 ml. ofpyridine is added to a mixture of 6 g. of chromic trioxide in 20 ml. ofpyridine. The reaction mixture is allowed to stand at room temperaturefor 15 hours, diluted with ethyl acetate and filtered through Celitediatomaceous earth. The filtrate is washed well with water, dried andevaporated to dryness to yield 2- tahydronaphth-Z-yl)-acetic acid whichmay be further purified by recrystallization from acetonezhexane.

In like manner, the foregoing procedure is used to prepare the 6'-oxocompound corresponding to the products of Example 9 and the reducedethanol derivative thereof via its selectively protected ethanolhydroxyl.

EXAMPLE i2 A mixture of l g. of the (6'-oxo-9',l0'-methano-l',

acid, 15 ml. of acetic anhydride and 0.2 g of sodium acetate is refluxedfor one hour. The reaction mixture is then poured into dilute sodiumbicarbonate solution to hydrolyze any excess anhydride. This mixture isextracted with' methylene chloride. The methylene chloride extracts arecombined, washed, dried evaporated and chromatographed to give the (6-acetoxy-9', l0'-methano-l ',4',5',8,9',lO'B-hexahydronaphth-2'-yl)acetic acid.

In like manner, the other enol esters of the present invention can beprepared by the use of the appropriate carboxylic acid anhydride, suchas the propionate, butyrate, valerate, and the like.

EXAMPLE 13 Y I A mixture of 3 g. of the (6'-oxo-9,l0'-methano-l ',4'-5,6 ,7' ,8 ,9 l0'B-octahydronaphth-2'-yl )acetic acid, about 2equivalents of zinc powder and 200 ml. of dry tetrahydrofuran arestirred for about two hours at 50-60C. Stirring is continued untilformation of zinc enolate is complete as checked'by thin layerchromatography. The mixture is allowed to stand and cool and thendecanted under anhydrous conditions. To the thus-obtained solution thereis added about 50 ml. of dimethyl sulfate and the mixture stirred. Thereaction mixture is then allowed to stand at room temperature untilformation of the enol ether is complete as checked by thin layerchromatography. The reaction mixture is then poured into water. Thismixture is extracted with methylene chloride. The methylene chlorideextracts are washed, dried, and evaporated and chromatographed to givethe (6'-methoxy-9',l0- methano-l ',4',5 ,8',9' l 0'B-hexahydronaphth-2'-yl)acetic acid.

In like manner, the other enol esters of the present invention can beprepared, such as the ethoxy, propyloxy, butyloxy, and the like.

' EXAMPLE l4 (6'-Acetoxy-9',l07-methano-l',4',5',8',9,l0'-hexahydronaphth-2'-yl)acetic acid methyl ester (200mg.) is dispersed in 6 ml. of dioxane at room temperature with stirring.To the resultant mixture is added 1 gram of2,3-dichloro-5,6-dicyano-l,4-benzoquinone with stirring while coolingthe reaction mixture to 25C. The resultant mixture is heated to theboiling point and maintained under reflux conditions for 4 hours. Afterthis time, the solution is cooled and poured into ethyl acetate. Theresultant mixture is filtered and the filtrate is washed twice withwater, dried over magnesium InlnAn sulfate, filtered through 10 gm.neutral alumina and evaporated to provide the 8-acetoxy-l,6-methano-[10]-annulene-3-acetic acid methyl ester product. This product can alsobe referred to as (l',6-methano-8- acetoxycyclodecapentaen-3 -yl)aceticacid.

In like manner, the other enol esters and ethers of the presentinventions (see Examples 12 and 13) are converted to the correspondingannulene products e.g. the methyl esters of 8-methoxyl ,6-methano-[l]-a.nnulen-3-acetic acid,

8-butyloxy-l ,6-difluoromethano-[ l0]-annulen-3- acetic acid,

2-( 8-methoxy- 1 ,6-difluoromethano-[ l0 ]-annulen-3- yl) ethanol,8-propionyloxy-l ,6-dichloromethano-[ l0]-annulen- 3-acetic acid,

8-propionyloxy-l ,6-methano-[ l0]-annulen-3-acetic acid,

8-ethoxy- 1 ,6-methano-[ l0 ]-annulen-3-acetic acid,

2-( 8-propyloxyl ,6-methano-[ l0]-annulen-3-yl)- ethanol,

2-( 8-ethoxyl ',6'-methano-[ l0]-annulen-3- yl)propionic acid,

2-( 8 -methoxyl ',6'-methano-[ l0]-annulen-3- yl)propionic acid, and

3-yl)propionic acid.

EXAMPLE 15 The procedures of Examples 8, 9, and 10 are performed uponthe 6-unsubstituted, -lower alkyl, and monocyclic lower alkyl compoundsof Examples 1, 2, and 3 to prepare the corresponding9',l0-bridgedl,4,5',8',9,l0-hexahydro-naphthalene methyl estercompounds. These compounds are subjected to treatment with benzoquinoneas described in Example 14 to prepare, for example, the methyl esters(l',6'- methano-[ l0]-annulen-3-yl)acetic acid, 1,6- dichloromethano-[l0]-annulen-3-yl)acetic acid, l ,6- dichloromethano-[l0]-annulen-3-yl)acetic acid, 1,6- difiuoro-[10]-annulen-3-yl)aceticacid, and the various 8-substituted compounds, e.g.(8-methyl-l,6-methanol0]-annulen-3-yl)acetic acid, (8-ethyl-l ,6-difiuoromethano-[10]-annulen-3-yl)acetic acid, 8- propyloxyl,6-difiuoromethano-[ l0l-annulen-3- yl)acetic acid, (8-cyclopropyll,6-methano-[ l0]-annulen-3-yl acetic acid and the like.

EXAMPLE 16 2-(9', l0-Dichloromethano-l',4,5',8,9',10'-hexahydronaphth-2'-yl)propionic acid methyl ester (1gram) is dispersed in 50 ml. of dioxane at room temperature. To theresultant mixture are added grams of2,3-dichloro-5,6-dicyano-l,4-benzoquinone at room temperature withstirring. The reaction mixture is then heated to the boiling point andmaintained under reflux conditions for 6 hours. The reaction mixture isthen chromatographed on 25 gm. of silica gel eluting with ether-hexaneto provide the 2-( l ',6' dichloromethano- 2',5 '-dihydro-[]-annulen-3'-yl)propionic acid.

2-( l ,6-dichloromethano-2,5'-dihydro-[ l0]-annulen-3-yl)-propionic acid(67 mg. is dispersed in ml. of methylene chloride at room temperature.The resultant solution is cooled to 80C. and, when arriving at thistemperature, 1 molar equivalent of bromine dichloromethano-[l0]-annulen-3-yl)propionic dispersed in 1.8 ml. of methylene chloride isslowly added thereto. After 10 minutes, the solution is evaporated andthe residue recrystallized from ether methanol (1:1) to provide the 2-(l',6'-dichloromethano-3,4'-dibromo-[ l0l-annulen-3 -yl )propionic acidwhich is dispersed in 6 ml. of dimethylforrnamide at room temperaturewith stirring. To the resultant solution is added 0.2 ml. ofdiazabicyclononene. After allowing this reaction mixture to stand for 3days at room temperature, the solution is poured into water, acidifiedwith dilute HCl and extracted with ether. The ether extracts areisolated and washed three times with water, and the washed materialdried over magnesium sulfate and evaporated to provide the 2-(l,6-

acid product.

EXAMPLE l7 2-(6'-methyl-9' l 0-difluoromethanol ,4,5 ,8-tetrahydronaphth-2-yl)propionic acid methyl ester (1 g.) is added to 10ml. of dioxane at room temperature with stirring. The resultant mixtureis maintained at 25C. and one chemical equivalent of tetrachloro-l,4-benzoquinone is added thereto with stirring. The temperature of thereaction mixture is then raised to the boiling point and maintainedunder reflux for 6 hours after which time it is poured into ethylacetate. The resultant mixture is washed with water and filtered throughneutral alumina. The filtrate is washed with water, dried and evaporatedto provide the methyl ester of 2-(8 '-methyll ,6'-difluoromethyl-2' ,5'-dihydrol0]-annulen-3-yl)propionic acid.

EXAMPLE 1 8 The product prepared as described in Example 17 is treatedwith bromine and the resultant compound dehydrobrominate as set forth inExample 16 above to prepare the 2-( 8-methyl-l ',6'-difiuoromethano-[l0]- annulen-3 '-yl )-propionic acid product.

EXAMPLE 19 The procedure of Example 17 is repeated using about twochemical equivalents of tetrachloro-l,4- benzoquinone to provide the2-(8'-methyl-l,6'- dichloromethano-[ l0]-annulen-3'-yl)propionic acidproduct, preferably after hydrolysis from the methyl ester.

EXAMPLE 20 In accordance with the foregoing methods, the respectivestarting compounds set forth in Column A below are reacted with therespective reactants set forth in Column B below to provide therespective product set forth in Column C below.

2-( l ',l -dimethyl-2-hydroxyethyl)-9, l O-methano- 1 ,4,5,8,9, lO-hexahydronaphthalene,

2-( l'-ethyl-1 '-methyl-2'-acetoxyethyl)-9, l 0- dichloromethano- 1,4,5,8,9, l O-hexahydronaphthalene,

2-( 1 '-ethyl-l -methyl-2'-carbamoylethyl)-9, l 0- methano- 1,4,5 ,8 ,9,l0-hexanydronaphthalene,

1-carbopropoxymethyl-9, l O-difluoromethano- 1,4,5 ,8,9, 1O-hexahydronaphthalene,

l-( 2'-hydroxyethyl )-9, l O-methanol ,4,5 ,8 ,9, lO-hexahydronaphthalene,

2-( 2'-n-butoxyethyl )-9, l O-dichloromethanol ,4,5,8,9,IO-hexahydronaphthalene,

2-carboxymethyl-9, l O-methariol ,4,5,8,9, lO-hexahydronaphthalene,

l ,4-benzophenone,

2,3-dichloro-5,6-dicyano-l ,4-benzoquinone,

1 ,2-benzoquinone,

tetrachlorol ,2-benzoquinone,

tetrachloro-l ,4-benzoquinone,

2,3-difluorol ,2-benzoquinone, 2,3-difluorol ,4-benzoquinone,

2,3-dicyanol ,2-benzoquinone, 2,3-dicyano-l ,4-benzoquinone,2,3-dichloro-5 ,6-dicyano-l ,4-benzoquinone,

EXAMPLE 21 the hydroxy containing annulene products hereof, for example,the propionate, the butyrates, the valerates, the caproates, theenanthates, and the caprylates.

EXAMPLE 23 Two milliliters of dihydropyran are added to a solution of lg. of l,6-methano-3-(2'-hydroxyethyl)-[l0]- annulene in l5 ml. ofbenzene. About 1 ml. is removed by distillation to remove moisture andmg. of ptoluenesulfonyl chloride is added to the cooled solution. Thismixture is allowed to stand at room temperature for 4 days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith etlierzhexane to yield [,6- methano-3-( 2'-tetrahydropyran-2'-yloxyethyl H 10]- annulene which is recrystallized from ether-hexane.

In like manner, the foregoing method can be utilized substitutingdihydrofuran for dihydropyran so as to o prepare the correspondingtetrahydrofuran-2-yloxy A solution of l g. of 3-carbomethoxymethyl-l,6-

methano-[ l0l-annulene in 50 ml. of tetrahydrofuran is added over 30minute period to a stirred suspension of l g. of lithium aluminumhydride in -50 ml. of anhydrous tetrahydrofuran and this mixture isheated at reflux for 2 hours. To the mixture are cautiously added 5 ml.of ethyl acetate and 2 ml. of water. Sodium sulfate is next added, themixture is filtered and the solid thus collected is washed with hotethyl acetate. The combined organic solutions are then evaporated toyield 1 ,6-methano-3-(2-hydroxyethyl)-[ l0]-annulene which may befurther purified through recrystallization from acetonezhexane.

EXAMPLE 22 A mixture of l g. ofl,6-methano-3-(2'-hydroxyethyl)-[l0-]-annulene l g. of p-toluenesulfonicacid monohydrate 50 ml. of acetic acid and 25 ml. of acetic anhydride isallowed to stand at room temperature for 24 hours, and then itis pouredinto water and stirred. This mixture is then extracted with methylenechloride and these extracts are dried and evaporated to yield 60compound. Similarly, the foregoing method can be used with the otherhydroxy annulene products hereof so as to prepare the correspondingethers thereof.

EXAMPLE 24 A solution of one chemical equivalent of 1,6--methano3-(2'-hydroxyethyl)-[l0]-annulene in 30 ml. of benzene is heatedto reflux and about 2 ml. removed by distillation to eliminate moisture.The mixture is cooled to room temperature and one chemical equivalent ofsodium hydride are added, followed by the dropwise addition of twochemical equivalents of cyclopentyl bromide in 10 ml. of benzene over aperiod of 20 minutes. The mixture is allowed to reflux for 20 hoursafter which time the precipitate of sodium bromide is removed byfiltration and the organic phase dried and evaporated to yieldl,6-methano-3-(2'- cyclopentyloxyethyl)-[l0]-annulene which is furtherpurified upon recrystallization from pentane. I

The foregoing method can be performed upon the other correspondingannulene products hereof so as to prepare the correspondingcyclopentyloxy compounds.

EXAMPLE 25 A solution of l g. ofl,6-difluoromethano-3-carboethoxy-methyl-[ l0l-annulene in 50 ml. ofethylene glycol is heated at reflux for 3 hours with a solution ofpotassium hydroxide in 1 ml. of water. The reaction mixture is thenpoured into ice water and the solid which forms is collected byfiltration, washed with water to neutrality and dried to yield 1,6-difluoromethanocarboxymethyl-[l0]-annulene which is recrystallized frommethylene chloridezether.

The foregoing method can be performed upon the other correspondingannulene ester products hereof so as to prepare the correspondingcarboxylic acid compounds.

EXAMPLE 26 To a solution of 10 g. ofl,6-difluoromethano-3-carboxymethyl-[ l0]-annulene in 200 ml. of ethanolis added the theoretical amount of potassium hydroxide dissolved in 200ml. of percent ethanol. The reaction mixture is then concentrated invacuum giving the' other metal salts contemplated herein are prepared.

EXAMPLE 27 A solution of 10 g. of3-carboxymethyl-8-methoxyl,6-dichloromethano-[ 10]-annulene in 50 ml. ofthionyl chloride is heated at reflux for 1 hour. Thereafter, thesolution is evaporated to dryness to give the corresponding acidchloride to which is added a concentrate ethereal ammonia solution. Theresultant solution is evaporated giving the amides of 1,6-dichloromethano-3-carboxymethyl-8-methoxy-[ 10]- annulene.

The foregoing method can be performed upon the other correspondingannulene products hereof so as to prepare the corresponding carboxylicacid amide compounds.

EXAMPLE 28 Two grams of (1,6-methano-8-acetoxy-[ l]-annulen-3-y1) aceticacid in 20 ml. of diethyl ether is added to an ethereal solution of 1.2molar equivalents of diazomethane. The resulting mixture is allowed tostand at 0C. for about one hour and then is evaporated under reducedpressure to yield the methyl ester of 1,6-methano-3-carbomethoxymethyl-8-acetoxy-[ l0]-annulene.

EXAMPLE 29 A solution of 6 g. of 1,6-difluoromethano-3-(2'-hydroxy-ethyl)-[]-annulene in 120 ml. of pyridine is added to a mixtureof 6 g. of chromic trioxide in ml. of pyridine. The reaction mixture isallowed to stand at room temperature for 15 hours, diluted with ethylacetate and filtered through Celite diatomaceous earth. The filtrate iswashed well with water, dried and evaporated to dryness to yield1,6-difluoromethano-3- formy1methyl-[ lO]-annuler1e.

EXAMPLE 30 EXAMPLE 31 1,6-Methano-l l0]-annulen-3-yl)-acetic acid methylester (0.05M) is dissolved in dimethyl sulfoxide ml.) containing sodiummethoxide (0.05M) and formaldehyde gas is passed in until an increase inweight of 3 grams has occurred. The mixture is stirred at roomtemperature for 6 hours and then 50 ml. of dilute HCl is added. Thesolution is extracted with ether and the extracts are washed, dried andevaporated to give 2-( l ,6 '-methano-[l0]-annulen-3-yl)-acrylic acidmethyl ester.

The foregoing methyl ester can be hydrolyzed via the method known per sesuch as with the aqueous sodium hydroxide to provide the correspondingacrylic acid compound.

EXAMPLE 32 A mixture of 7 g. of methylene iodide and 3 g. of zinc-coppercouple in 15 ml. of anhydrous ether is heated at reflux under nitrogenfor 3 hours. The mixture is then cooled and 2 g. of2-(l',6'-methano-[10]- annulen-3-yl)-acrylic acid methyl ester areadded. This mixture is refluxed for 2 hours and is then poured into 200ml. of 2 percent aqueous sodium carbonate and extracted twice with ml.portions of ether. These extracts are dried over sodium sulfate andevaporated under reduced pressure. The residue is held at 0.01 mm. toremove any unreacted methylene iodide and then recrystallized fromhexane to yield 1,6- methano-3-( 1 ,1 '-ethylenecarbomethoxymethyl)-[l0]- annulene.

EXAMPLE 3 3 (1,6 Methano-[ l0]-annulen-3-yl)-acetic acid methyl ester(0.1 M) is dissolved in glyme 100 ml.) and sodium hydride (0.1 M) isadded followed by 1,4- dibromobutane (0.1M). The mixture is heated to90C. for four hours and then a further 0.1 M sodium hydride is added.The mixture is heated to 90C. for a further three hours, and then iscooled. One liter of water is added to the resultant mixture and thesolution is extracted with ether. The extracts are washed, dried andevaporated to give l,6-methano-3-( 1 ',l'-butylene carbomethoxymethyl l0l-annulene.

Upon base hydrolysis the corresponding acid is prepared. By substituting1,3-dibromopropane and 1,5- dibromopentane for 1,4-dibromobutane in theabove, the corresponding 1,l'-propylene and l,1'-pentylene products arerespectively prepared.

EXAMPLE 34 To a mixture of 22 grams of the methyl ester of 1,6-methano-3-( 1-carbomethoxymethy1-[ l0]-annulene, 1 equivalent of sodiumhydride and m1. of 1,2- dimethoxyethane, there is added one equivalentof methyl iodide. The reaction mixture is allowed to stand for severalhours and then diluted with ethanol and water. Mixture is then extractedwith methylene chloride. The methylene chloride extracts are combinedwashed and dried and evaporated to give 1,6- methano-3-( l'-carbomethoxyeth-l "-yl)-[ 10]-annulene.

The foregoing procedure is repeated using two equivalents each of sodiumhydride and methyl iodide so as to prepare the corresponding1,6-methano-3-(2- carbomethoxyprop-2-yl)-[ l0]-annulene or 2-( l ,6-methano-[ 10]-annulen-3'-yl) isobutyric acid.

By substituting other lower alkyl iodides for methyl iodide in the aboveprocedures, there are prepared the EXAMPLE 35 A solution of g. ofZ-naphthylacetic acid in 100 ml. of ethanolzether (1:1) is added to g.of sodium in 500 ml. of liquid ammonia at -7 8. After about 1 hour,excess sodium is destroyed by the addition of ammonium chloride andabout 50 ml. of water is added. The

reaction mixture is then allowed to rise to room tem- 15 perature andthen about 200 ml. of water followed by about 400 ml. of ether is added.The ether layer is separated, washed, dried over magnesium sulfate andevaporated to give l,4,5,8-tetrahydro-2-naphthylacetic :tra, acid whichcan be purified by recrystallization from aqueous methanol.

By repeating the above procedure using 2-(6'- methoxy-2-naphthyl)ethanolas the starting material, there is obtained 2-(6'-methoxy-1 ',4 ,5,8-tetrahydro- 2-naphthyl) ethanol.

EXAMPLE 36 A. A solution of 1 g. of l',4,5,8-tetrahydro-2-naphthylacetic acid in dry tetrahydrofuran is refluxed stand at roomtemperature for 15 hours. The mixture is then poured into water andextracted several times with ethyl acetate. The ethyl acetate extractsare combined, 40

washed with dilute hydrochloric acid and water, dried and evaporated .togive the acetate of 2-(l',4',5',8t

The procedure of Part A above is repeated using 6-metnoxy-2-naphthylacetic acid as the starting material and there isobtained. 2-(6-methoxy-2- naphthyl)ethanol.

As an alternative to the procedure of Part A of this example, prior toreduction, the acid can be converted into the methyl ester as bytreatment with diazomethane or the like, and the thus-obtained methylester then converted into the alcohol by treatment with lithium aluminumhydride at about room temperature for about two hours.

EXAMPLE 37 A. A solution of 5 g. of theacetate of 2-( l ',4'-5,8-tetrahydro-2-naphthyl)ethanol in ml. of diglyme heated to about there isadded slowly a solution of 1.5 equivalents of sodium trichloroacetate in100 ml.

of diglyme over a period of about 1 hour. The reaction mixture is thenallowed to cool to about room temperature and is then diluted with waterand ethyl acetate. 5

The ethyl acetate layer is separated, washed, dried over magnesiumsulfate and evaporated to give a mixture containing the acetate of2-(9',l0'-dichloromethylenel ',4' ,5,8',9', l 0-hexahydro-2'-naphthyl)ethanol which is separated by chromatography.

By using sodium chlorodifluoroacetate in place of sodiumtrichloroacetate in the above procedure, there is obtained the acetateof 2-(9,l0'-difluoromethylenel',4' ,5 ,89' l0-hexahydro-2'-naphthyl)ethanol.

B. A solution of 0.75 g. of the acetate of 2-(9,l0'- dichloromethylene-l,4 ,5 ,8 ,9 l 0-hexahydro-2'- naphthyl)-ethanol in 50 ml. of ether isadded to a solution of 500 mg. of sodium in ml. of liquid ammonia withstirring. After 2 hours, ammonium chloride is added until the blue coloris discharged and the ammonia allowed to evaporate. Extraction withether affords 2-(9', l 0'-methylene-l ',4',5,8',9',l0'-hexahydro-2'-naphthyl)ethanol which can be further purifiedby chromatography.

EXAMPLE 3 8 A. Two milliliters of dihydropyran are added to a solutionof l g. of 2-(9',l0'-methylene-l',4,5',8',9',l0'-hexahydro-2'-naphthyl)ethanol in 15 ml. of benzene. About 1 ml. isremoved by distillation to remove moisture and 10 mg. ofp-toluenesulfonic acid is added to the cooled solution. This mixture isallowed to stand at room temperature for 4 days,and then washed withaqueous sodium carbonate solution an water, dried and evaporated. Theresidue is chromatographed on neutral alumina, eluting with hexane, toafford the tetrahydropyran-2"-yl ether of 2-(9',l0- methylene-l ',4' ,5',-8 ,9 l 0-hexahydro-2-naphthyl) ethanol.

B. To a solution of l g. of the above tetrahydropyran- 2"-yl ether in100 ml. of carbon tetrachloride containing a trace of pyridine, there isadded 2 molar equivalents of bromine in 50 ml. of carbon tetrachloride.The reaction mixture is allowed to stand at room temperature for about20 hours. The reaction mixture is washed, dried and evaporated to givethe tetrahydropyran-2"-yl ether of 2-(2,3,6',7-tetrabromo-9' l0'-methylenedecahydro-2 -naphthyl ethanol.

One gram of the above 2,3,6,7-tetrabromo compound is dissolved in 15 ml.of dry tetrahydrofuran and then about 4 g. of potassium t-butoxide isadded. The reaction mixture is stirred for about 3 hours and then it isdiluted with water and ether. The ether layer is separated, washed,dried and evaporated to give the tetrahydropyran-2"-yl ether of2-(l',6'-methanocyclodecapentaen-3 '-yl )ethanol.

EXAMPLE 39 A. To a solution of l g. of the tetrahydropyran-2"-yl etherof 2-( l ',6-methanocyclodecapentaen-3'- yl)ethanol in 30 ml. of aceticacid is added 0.5 ml. of 2N hydrochloric acid. The mixture is allowed tostand about 5 hours at room temperature and then diluted with water andextracted with methylene chloride. The methylene chloride extracts arewashed with water to neutrality, dried and evaporated to afford 2( l,6'- methanocyclodecapentaen-3 '-yl )ethanol.

, B. A mixture of l g. of 2-(]',6'-methanocyclodecapentaen-3'-yl)ethanol and 50 ml. of pyridine isadded to a mixture of 1 molar equivalent of chromium trioxide in 20 ml.of pyridine. The reaction mixture is allowed to stand at roomtemperature for 15 hours,

101MB. 1 mm diluted with ethyl acetate and filtered. The filtrate iswashed well with dilute hydrochloric acid and water, dried andevaporated to give 2-(l,6-methanocyclodecapentaen-3 '-yl )ethanal l,6-methanocyclodecapentaen-3-ylacetaldehyde].

C. The procedure of Part B is repeated using the above prepared aldehydeas the starting material and there is obtainedl,-methanocyclodecapentaen-3- ylacetic acid.

EXAMPLE 40 The procedure of Example 38 (Part B) is repeated using theacetate of 2-(9',l0'-dichloromethylene-l ',4, ,8',9,10-hexahydro-2-naphthyl)ethanol and the acetate of2-(9',l0'-difluoromethylene-l',4',5',8',9',l0'-hexahydro-2'-naphthyl)-ethanol as the starting material in placeof the tetrahydropyran-2' -yl ether of2-(9',l0'-methylene-l',4',5',8',9',l0'-hexahydro-2'- naphthyl)ethanoland there is obtained 2-(l',6'-dichloromethanocyclodecapentaen-3'-yl)ethanol and 2-( l',6'-difluoromethanocyclodecapentaen-3'- yl)ethanol, respectively.

By repeating the procedure of Example 39 (Part B) using 2-( l,6-dichloromethanocyclodecapentaen-3'- yl)ethanol and 2-(1',6-difluoromethanocyclodecapentaen-3-yl)ethanol as the startingmaterial, there is obtained 2-( l',6'-dichloromethanocyclodecapentaen-3'- yl)ethanal and 2-(1',6-difluoromethartocyclodecapentaen-3'-yl)ethanal, respectively, whichare subjected to the procedure of Example 38 (Part C) to afiord thecorresponding acids, i.e. l,6-dichloromethanocyclodecapentaen-3-ylaceticacid and l ,6- difluoromethanocyclodecapentaen-3-ylacetic acid,

respectively.

EXAMPLE 41 To a solution of l g. of1,6-methanocyclodecapentaen-3-ylacetic acid in 25 ml. of ethanol, thereis added with stirring an aqueous solution of a molar equivalent ofpotassium bicarbonate. This mixture is stirred until the evolution ofcarbon dioxide ceases and then the mixture is evaporated to furnish thepotassium salt of l ,6-methanocyclodecapentaen-3-ylacetic acid.

By using sodium bicarbonate in the above procedure, the correspondingsodium salt is obtained.

Alternatively, salts can be prepared by titrating a solution of the freeacid with an alcohol solution of the appropriate alkali metal alkoxideto neutrality.

EXAMPLE 42 A mixture of l g. of the sodium salt of1,6-methanocyclodecapentaen-3-ylacetic acid, 3 ml. of methyl iodide andml. of dimethylacetamide is stirred in the dark for 5 hours. Excessmethyl iodide is removed by evaporation under reduced pressure. Themixture is then poured into water and extracted several times withether. The ether extracts are combined, washed, dried and evaporated togive the methyl ester of 1,6- methanocyclodecapentaen-3-ylacetic acid.

By using other lower alkyl iodides in place of methyl iodide in theabove procedure, the corresponding lower alkyl esters are obtained.

Alternatively, the free acids can be converted into lower alkyl estersby treatment with a lower diazoalkane such as diazomethane, diazoethane,and the like, in ether for a few hours.

EXAMPLE 43 To a mixture of 22 g. of the methyl ester of 1,6-methanocyclodecapentaen-3-ylacetic acid, 2.5 g. of sodium hydride and150 ml. of l,2-dimethoxyethane, there is added 25 g. of methyl iodide.The reaction mixture is allowed to stand for several hours and is thendiluted with ethanol and water.'The mixture is then extracted withmethylene chloride. The methylene chloride extracts are combined,washed, dried and evaporated to give the methyl ester of 2-(l',6'-methanocyclodecapentaen-3 '-yl )propionic acid.

EXAMPLE 44 A mixture of 25 g. of the methyl ester of 2-( l ,6-methanocyclodecapentaen-3-yl)propionic acid, 15 g. of sodium carbonate,200 ml. of methanol and 25 ml. of water is allowed to stand for 24hours. The reaction mixture is acidified by the addition of dilute HCland then extracted with methylene chloride. The methylene chlorideextracts are combined, washed, dried and evaporated to give 2-(1',6-methanocyclodecapentaen- 3-yl)propionic acid.

EXAMPLE 45 A mixture of 2 g. of 2-(6'-methoxy-l',4',5',8'-tetrahydro-2'-naphthyl)ethanol and 35 ml of methanol isheated to reflux and 3.5 of acetic acid added. This mixture'is refluxedfor about 15 minutes and then allowed to cool. The mixture is thendiluted with water and extracted with methylene chloride. The methylenechloride extracts are combined and then washed, driedahydro-2'-naphthyl)ethanol which is converted into 2- (6'-oxo-9,l0-dichloromethylene-l ,4',5 ,6,7' ,8 ,9,lO"-octahydro-2'-naphthyl)ethanol and 2-(6'-oxo-9,lO'A-difluoromethylene-l ',4',5',6',7',8',9', lO'B-octahydro-2'-naphthyl)ethanol using the procedure of Example 37(Part A).

EXAMPLE 46 EXAMPLE 47 A mixture of 2.0 g. of the tetrahydropyran-2"-ylether of 2-(6'-oxo-9,l0'-methylene-l',4',5.6',7',8',9',10-octahydro-2-naphthyl)ethanol. 2.3 g. of cupric bromide and 200 ml.of methanol is refluxed for 24 hours. The reaction mixture is pouredinto water and the resulting mixture extracted with chlorofonn. Theorganic extracts are dried over magnesium sulfate and evaporated. Theresidue is chromatographed on silica gel to give thetetrahydropyran-2"-yl ether of 2-(6'- oxo-7'-bromo-9' l '-methylene-l',4' ,5 ,6',7',8',9

l 0'-octahydro-2'-naphthyl)ethanol.

A mixture of l g. of the above 7-bromo compound, 1.2 g. of lithiumbromide and 100 ml. of dimethylformamide is stirred at about 90 for 20hours. The reaction mixture is poured into water and extracted withether. The ether extracts are washed well with-water, dried andevaporated. The residue is chromatographed on alumina to yield thetetrahydropyran-2"-yl ether of 2-(6'-oxo-9',l0'-methylene-1',4',5',6',9,10'-hexahydro-2-naphthyl)ethanol.

As an alternative to the above procedure, the 7,8- dehydro of thetetrahydropyran-2"-yl ether of 2-(6'- 7 and 0.2 g. of sodium acetate isrefluxed for 1 hour. The

reaction mixture is then poured into dilute sodium bicarbonate solutionto hydrolyze any excess anhydride. This mixture is extracted withmethylene chloride. The methylene chloride extracts are combined,washed, dried and evaporated to give the tetrahydropyran-2"-yl ether of2-(l',6-methano-8'- acetoxycyclo-decatetraen-3'-yl)ethanol.

EXAMPLE 49 A mixtureof 2 g. of the tetrahydropyran-2"-yl ether 2-( l',6'-methano-8 -acetoxycyclodecatetraen-3 yl)ethanol and 1 molarequivalent of N-bromosuccinimide in 100 ml. of carbon tetrachloride isrefluxed for about 1.5 hours. The mixture is cooled and filtered. Thefiltrate is concentrated and to the residue there is added 0.5 g. ofcalcium carbonate and 25 ml. of dimethylformamide. The reaction mixtureis heated at reflux for about 30 minutes and then cooled. The mixture isfiltered and filtrate evaporated to givethe tetrahydropyran-2"-yl etherof 2-(l',6'-methano-8- acetoxycyclodecapentaen-3'-yl)ethanol which ispurified by chromatography.

The tetrahydropyran-27'-yl ether of 2-(l',6-methano-8'-acetoxycyclodecapentaen-3'-yl)ethanol is subjected to theprocedures of Example 39 to give 2- l ,6-methano-8'-acetoxycyclodecapentaen-3 yl)ethanol, 2-( l',6-methano-8'-acetoxycyclodecapentaen-3'-yl)ethanol, and.l,6-methano-8-acetoxycyclodecapentaen-3-ylacetic acid, respectively.

EXAMPLE 50 One gram of the tetrahydropyran-2"-yl ether of 2- l',6-methano-8-acetoxycyclodecapentaen-3 yl)ethanol is allowed to standat room temperature for l hours with l g. of potassium bicarbonate in 10ml. of water and 90 ml. of methanol. The reaction mixture is and 48,there is obtained the tetrahydropyran-2"-yl ether of 2'-( l,6-dichloromethano-8'-acetoxycyclodecatetraen-3'-yl)-ethanol and thetetrahydropyran-2"-yl ether of 2-( l ',6-

difluoromethano-8 '-acetoxycyclodecatetraen-3 '-yl) ethanol,respectively, which a further treated according to the procedures ofExample 49 to give thetetrahydropyran-2' '-yl ether of 2-( l ',6-dichloromethano-8'-acetoxycyclodecapentaen-3'- yl)ethanol, 2-(l',6'-dichloromethano-8 '-acetoxycyclodecapentaen-3-yl)-ethanol, 2-(1',6-dichloromethano- 8 '-acetoxydecapentaen-3 '-yl )ethanol, and l ,6-dichloromethano-8-acetoxycyclodecapentaen-3- ylacetic acid and thetetrahydropyran-2"-yl ether of 2- l',6-difluoromethano-8'-acetoxycyclodecapentaen- 3-yl)ethanol, -2-( l',6-difluoromethano-8'-acetoxycyclodecapentaen-3'-yl)ethanol, 2-( l ,6'-difluoromethano-8 '-acetoxycyclodecapentaen-3 '-yl ethanal, and l,6-difluoromethano-8-acetoxycyclodecapentaen-3-ylacetic acid,respectively.

By repeating Example 50 using as the starting material thetetrahydropyran-2"-yl ether of 2-(l',6'-dichloromethano-8'-acetoxycyclodecapentaen-3'- yl)ethanol and thetetrahydropyran-2"-yl ether of 2-1,6-difluoromethano-8-acetoxycyclodecapentaen- 3'-yl)'ethanol, there isobtained 2-(l,6'- dichloromethano-8'-methoxycyclodecapentaen-3'-yl)ethanol, 2-( 1 ,6'-dichloromethano-8'-methoxycyclodecapentaen-3 -yl)ethanal and l ,6- dichloromethano-8-methoxycyclodecapentaen-3- ylaceticacid and 2-( l,6'-difluoromethano-8-methoxycyclodecapentaen-3 '-yl)-ethanol, 2-( l ',6 difluoromethano-8-methoxycyclodecapentaen-3'-yl)ethanal and l,6-difluoromethano-8-methoxycyclodecapentaen-3-ylaceticacid, respectively.

By using the procedure of Example 42, 1,6-difluoromethano-8-methoxycyclodecapentaen-3- ylacetic acid andl,6-difluoromethano-8-methoxycyclodecapentaen-3-ylacetic acid areconverted into the corresponding methyl ester. The thus-obtained methylesters are alkylated using the procedure of Example 43 and thenhydrolyzed using the procedure of Example 44 to afiord2-(l',6'-dichloromethano-8- methoxycyclodecapentaen-3 '-yl)-propionicacid and 2- l,6-difluoromethano-8-methoxy-cyclodecapentaen-3'-yl)propionic acid,respectively.

EXAMPLE 52 A suspension of l g. of 2-(8-methoxy-l ',6-methano-cyclodecapentaen-3-yl)propionic acid in 10 ml. of 48 percentaqueous hydrofluoric acid is stirred at 0C. for about minutes. Thereaction mixture is diluted with water and ethyl acetate. The ethylacetate layer is washed, dried and evaporated to dryness under reducedpressure and the residue chromatographed to give2-(6'-oxo-9',l0'-methylene-5 ,6,9', l 0'-tetrahydro-Z'-naphthyl)propionic acid.

A mixture of l g. of 2-(6'-oxo-9',l0'-methylene- 5 ,6 .9.10'-tetrahydro-2'-naphthyl)propionic acid, 15 ml. of acetic anhydrideand 0.2 g. of sodium acetate is refluxed for about 1 hour. The reactionmixture is then poured into water to hydrolyze any excess anhydride.Thereafter, the mixture is extracted with methylene chloride. Themethylene chloride extracts are combined, washed, dried and evaporatedto give 2-(8'- then concentrated under reduced pressure and dried. Theresidue is taken up in about ml. of anhydrous dioxane and to thismixture is added 1 ml. of methylorthoformate and a trace ofp-toluenesulfonic acid. The mixture is stirred at room temperature forabout minutes and then allowed to stand at room temperature for about 30minutes. The mixture is diluted with water and shaken and then extractedwith methylene chloride. The methylene chloride extracts are combined,washed, dried and evaporated to give 2- l ',6-methano-8'-methoxycyclo-decapentaen-3 yl)ethanol which is subjected to theprocedures of Example 39 (Parts B and C) to give the correspondingaldehyde and acid.

EXAMPLE 51 By subjecting the tetrahydropyran-2"-yl ether of 2- (6-oxo-9'l O'-dichloromethylene-l ',4',5',6,7,8, 9',l0 octahydro2'-naphthyl)ethanol and the tetrahydropyran-2"-yl ether of2-(6'-oxo-9,l0- difluoromethylene-l ,4',5 ,6 ,7',8',9' ,lO'B-octahydro-2'-naphthyl)ethanol to the processes of Examples 47 acetoxy-l',6'-methanocyclodecapentaen-3 yl)propionic acid.

By repeating the process of this Example using 2-(8'- methoxyl,6-difluoromethanocyclodecapentaen-3 yl)propionic acid and2-(8'-methoxy-l',6'- dichloromethanocyclodecapentaen-3'-yl)propionicacid as the starting materials, there is obtained 2-(8'- acetoxy-l',6-difluoromethanocyclodecapentaen-3 yl)propionic acid and2-(8'-acetoxy-l ,6'- dichloromethanocyclodecapentaen-3'-yl)propionicacid, respectively.

EXAMPLE 5 3 2-(6'-methoxy-l ',4',5,8'-tetrahydro-l '-naphthyl)-propanol, prepared from 2-(6'-methoxy-l naphthyl)propanol using theprocedure of Example 35, is converted into 2-(6'-oxo-l',4'5',6',7,8'-hexahydrol'-naphthyl)propanol which is transformed into2-(6'- oxo-9',l0'-dichloromethylene-1',4',5,6',7,8',9',IOB- octahydro-l'-naphthyl)propanol and 2-(6'-oxo-9,10'- difluoromethylene-l ,4',5 ,6,7,8' ,9 l O'B-octahydrol-naphthyl) propanol using the procedures ofExample 45.

By subjecting2-(6'-oxo-9',lO'-dichloromethylenel'-4',5',6',7',8',9',l0'-octahydro-1'-naphthyl)propanol to the procedure of Example 38 (Part A), there isobtained the corresponding tetrahydropyran-Z' '-yl ether which isreduced using the procedure of Example 37 (Part B) to afford thetetrahydropyran-2-yl ether of 2-(6-hydroxy-9',l0- methylene-l ',4',5',6,7',8',9',IO'B-octahydro-l naphthyl)propanol which is oxidized usingthe procedure of Example 39 (Part B) to afford the tetrahydropyran-2"-ylether of 2-(6-oxo-9,l0'- methylene-l',4',5',6, 7',8,9',l0'-octahydro-l'-naphthyl)propanol.

The tetrahydropyran-2"-yl ether of 2-( 6'-oxo-9, l 0'- methylene-l',4,5',6',7',8,9',IO'B-octahydro-l naphthyl)-propanol is dehydrogenatedusing the can be By subjecting the tetrahydropyran-2"-yl ether of 2- 1',6-methano-8'-acetoxycyclodecapentaen-2- yl)propanol to the process ofExample 50, there is obtained 2-( 1,6-methano-8-methoxycyclodecapentaen-2-yl)propanol which is oxidized tothe corresponding aldehyde and acid, i.e. 2-( l ',6'-methano-8-methoxycyclodecapentaen-2'-yl)propanal and 2-( l ,6'-methano-8'-methoxycyclodecapentaen-2- yl)propionic acid, using theprocedure of Example 39 (Parts B and C).

EXAMPLE 54 A. The tetrahydropyran-2"-yl ether of 2-(6'-oxo-9',l0-dichloromethylene-l ,4',5,6',7',8',9,1 octahydro-l'-naphthyl)propanol is dehydrogenated using the procedure of Example 47to obtain the tetrahydropyran-2"-yl ether of 2-(6'-oxo-9',l0'-dichloromethylene-l ',4,5',6' ,9,l0'-hexahydrol naphthyl)propanol whichis subjected to the procedure of Examples 48 and 49 to give thetetrahydropyran-2"- yl ether of2-(l',6'-dichloromethano-8-acetoxycyclodeca-3 ,6 ,8 l 0'-tetraen-2 '-yl)propanol, the tetrahydropyran-2"-yl ether of 2-( l ,6'-dichloromethano-8 '-acetoxycyclodecapentaen-2'-yl propanol, 2-( l,6-dichloromethano-8 '-acetoxycyclodecapentaen-2-yl)propanol, 2-( l ,6'-dichloromethano-S'-acetoxycyclodecapentaen-2'- yl)propanol and 2-( l',6'-dichloromethano-8'-acetoxycyclodecapentaen-2-yl)propionic acid.Using the procedure of Example 50, the thus-obtained 8'-acetoxycompounds can be converted into the corresponding 8 '-methoxy compounds.

B. By use of the procedure of Example 37 (Part A),2-(6'-oxo-l,4',5',6',7',8'-hexahydro-l'- naphthyl)pr0panol is convertedinto 2-(6 oxo-9',l0'- difluoromethylene-l ',4',5 ,6 ,7',8',9','lO'B-octahydrol'-naphthyl)propanol which is etherified using dihydropyranto afford the corresponding tetrahydropyran-2"-yl ether. Thetetrahydropyran-2"- yl ether of 2-(6'-oxo-9',l0'-difluormethylene-l ,4'.5,6',7,8,9,l0-octahydro-l'-naphthyl)propanol is further processedaccording to the procedure of Part A of this Example in place of thetetrahydropyran-2"-yl ether of 2-(6-oxo-9,l0'-dichloromethylene-l,4',

procedure of Example 47 to give the tetrahydropyran-5,6,7,8,9,l0-octahydro-l '-naphthyl)propanol and the corresponding9,l0'-difluoromethylene compounds and l ,6-difluoromethano compounds.

2-(1 ',6'-methano-8'-acetoxy- I EXAMPLE 55 The process of Example 35 isrepeated using 1- naphthyl-acetic acid as the starting material andthere is obtained l,4,5,8-tetrahydro-l-naphthylacetic acid which isconverted into the acetate of 2-(l',4',5',8'tetrahydro-l'-naphthyl)-ethanol by the procedure of Example 36. Thiscompound is processed according to the methods of Example 37 to give theacetate of 2- (9',l0'-dichloromethylene-l',4',5',8,9',l0'-hex- Yahydro-l'-naphthyl)ethanol, the acetate of 2-(9',l0'-difluoromethylene-l ',4' ,5 ,8 ,9 l -hexahydro-l naphthyl)-ethanol and2-(9',l0'-methylene-l ',4',5',8 ,9, i 0-hexahydrol- -naphthyl)ethanol.The process of Example 38 is then repeated using as the startingmaterial 2-(9',l0'-methylene-l',4,5',8',9',l0-hex-.ahydro-l'-naphthyl)ethanol and there is-obtained as the final product,the tetrahydropyran-Z' '-yl ether of 2-1,6-methanocyclodecapentaen-2'-yl)ethanol which can be treated accordingtothe procedure of Example 39 to obtain the corresponding free alcohol,aldehyde and acid, i.e. 2-(l,6'-methanocyclodecapentaen2'- yl)-ethanol,2-( l f,6-methanocyclodecapentaen-2'- yl)ethanal and 1,6-methanocyclodecapentaen-2- ylacetic acid.

By repeating this example using 2-(l'- EXAMPLE 5 6 A solution of l g. of2-(8-methoxy-l,6-methanocyclodecapentaen-3-yl)propionic acid, 2 ml. ofthionyl chloride in 20 ml. of benzene is held at reflux for about 2hours. The reaction mixture is cooled and evaporated. The residue isdissolved in anhydrous dioxane and the solution saturated with a streamof anhydrous ammonia. Water is then added after about 20 hours and themixture evaporated under reduced pressure. The residue is taken up inmethylene chloride washed with water dried and evaporated to give 2-(8'-methoxy-l ,6-methanocyclodecapentaen-3 yl)propionic acid amide.

EXAMPLE 57 A mixture of-l g. of2-(8'-methoxy-l,6-methanocyclo-decapentaen-3'-yl)propanol, 3 ml. ofpyridine and 3 ml. of acetic anhydride is allowed to stand at roomtemperature forabout hours. The mixture is then poured into water andextracted with ethyl acetate. The, ethyl acetate extracts are combined,washed with dilute hydrochloric acid and water, dried and evaporated togive the acetate of 2-(.8'-methoxyl',63'-yl)propanoi.

Similarly, by using an equivalent amount of other lower carboxyiicanhydrides such as propionic an- 34 hydride, n-butyric anhydride,n-caproic anhydride, trimethylacetic anhydride, trichloroaceticanhydride, and the like, in place of acetic anhydride, the correspondingesters are obtained.

EXAMPLE 5 8 A mixture of l g. of the methyl ester of 2-(8'- methoxy-l',6-methanocyclodecapentaen-3'- yl)propionic acid and 20 ml. ofanhydrous tetrahydrofuran is cooled to -C. in a dry iceacetone bath andtreated with a previously cooled soution of 0.6 g. of lithium aluminumhydride in 20 ml. of anhydrous tetrahydrofuran. The reaction mixture isthen allowed to warm to room temperature and is then heated at refluxfor about 15 minutes. The reaction mixture is then cooled and pouredinto ice water and extracted several times with ethyl acetate. The ethylacetate extracts are combined, washed with water to neutrality, driedand evaporated to yield 2-(8'-methoxyl ,6'-methanocyclodecapentaen-3'-yl )propanol.

EXAMPLE 59 A mixture of 3 g. of the methyl ester of 2-(8'- methoxy-l',6'-methanocyclodecapentaen-3 yl)propionic acid, 1 g. of sodiummethoxide, 1.5 g. of hydroxylamine hydrochloride and 50 ml. of methanolis allowed to stand for about 16 hours. The mixture is then filtered andthe filtrate evaporated. The residue is neutralized by the addition ofaqueous 1N hydrochloric acid and extracted with ether. The etherextracts are combined, washed with water, dried and evaporated to yield2-( 8' -methoxy-1 ',6-methanocyclodecapentaen- 3'-yl) propionhydroxamicacid.

EXAMPLE 60 A mixture of l g. of2-(8-methoxy-l',6-methanocyclodecapentaen-3'-yl)propanol, l g. of sulfurtrioxide, trimethylarnine complex and 40 ml. of pyridine is stirred at40 C. for 2% days. The mixture is then poured into about 200 ml. ofsaturated sodium bicarbonate solution and extracted with ethyl acetatefollowed by extraction with n-butanol. The n-butanol extracts arecombined, dried over sodium sulfate and evaporated under reducedpressure to yield a residue which is taken up in methanol and stirredfor about 10 minutes with a carboxylic acid ion-exchange resin(Amberlite lRC-50, acid cycle). The mixture is filtered and the filtrateevaporated under reduced pressure to yiel 2-( 8 '-methoxy-l',6'-methanocyclodecapentaen- 3'-yl)propanol 2-sulfate monosodium salt.

EXAMPLE 61 A mixture of 2 g. of2-(8'-methoxy-l',6-methanocyclodecapentaen-3'-yl)propanol and 2 molarequivalents of B-cyanoethyl phosphate in pyridine is combined withpyridine solution of 8 molar equivalents ofN,N'-dicyclohexylcarbodiimide and the reaction mixture is allowed tostand at room temperature for 24 hours. The reaction mixture is dilutedwith a small amount of water and allowed to stand at about 5C. for 2days. The mixture is then evaporated to dryness under reduced pressureand the residue taken up in about 35 ml. of aqueous methanol (lzl Thismixture is treated with about 12 ml. of 5 percent aqueous sodil the umhydroxide solution and after about 1 hour at room temperature, it isconcentrated under reduced pressure, diluted with 30 ml. of aqueousmethanol, concentrated and mixed with 75 ml. of water. This mixture isfiltered and the filtrate is treated batchwise and then columnwise withan excess of a sulfonic acid ionexchange resin (H form) to yield2-(8'-methoxy-l ,6- methanocyclodecapentaen-3-yl)propanol 2- phosphate.

EXAMPLE 62 The procedure of Examples 41 and 42 is repeated using 1,6-dichloromethanocyclodecapentaen-3- ylacetic acid andl,6-difluoromethanocyclodecapentaen-3-ylacetic acid to obtain thecorresponding methyl ester which is alkylated according to Example 9 toyield methyl ester of 2-( l',6-dichloromethanocyclodecapentaen-3'-yl)propionic acid and the methylester of 2-( l ',6-difluoromethanocyclodecapentaen-3 yl)-propionic acid,respectively. The thus-obtained methyl ester can be hydrolyzed using theprocedure of Example 44 to obtain the free acids. Alternatively, themethyl esters can be reduced using the procedure of Example 36 or 58 toobtain the corresponding alcohols, i.e. 2-( l',6'-dichloromethanocyclodecapentaen-3 yl)propanol and 2-( l,6'-difluoromethanocyclodecapentaen-3'-yl)propanol, which can beoxidized using the procedure of Example 5 to the corresponding aldehyde.

EXAMPLE 63 According to the procedure of Example 42, 1,6-methano-8-methoxycyclodecapentaen-3-ylacetic acid is converted into thecorresponding methyl ester. This methyl ester is alkylated according tothe method of Example 43 to give the methyl ester of2-(8'-methoxyl,6'3'-yl)propionic acid which is hydrolyzed according tothe method of Example 44 to yield 2-(8-methoxy-l,6'-methanocyclodecapentaen-3-yl)propionic acid.

EXAMPLE 64 To a solution of l g. of 2-(8'-methoxy-l',6-methanocyclodecapentaen-3'-yl)propanol and 25 ml.

of benzene there is added 2 ml. of 4'-methoxy-5,6-

be purified by chromatography.

EXAMPLE 65 A mixture of l g. of8-acetoxy-l,6-methanocyclodecapentaen-3-ylacetic acid and 4 ml. ofoxalyl chloride in benzene is heated at reflux under anhydrousconditions for two hours. The solution is evaporated under vacuum, takenup in benzene and again evaporated to yield 8-acetoxyl,6-methanocyclodecapentaen-3-ylacetic acid chloride which is treatedwith anhydrous ammonia to yield 2-(8'-acetox- 316 y-l',6-methanocyclodecapentaen-3 '-yl )propionic acid amide.

To a cooled solution of 1 g. of 2-(8-acetoxy-l ',6-methanocyclodecapentaen-3'-yl)propionic acid chloride and ml. oftetrahydrofuran is added one molar equivalent of lithium tri-t-butoxyaluminum hydride and the mixture allowed to stand-for about 12 hours atroom temperature. The mixture is diluted with water, concentrated undervacuum and again diluted with water. This mixture is extracted withethyl acetate and the ethyl acetate extracts are combined, dried andevaporated to give 2-(8'-acetoxy-l',6'-methanocyclodecapentaen-3-yl)propanol. The thus-obtained aldehydeis reduced using a molar equivalent of lithium tri-t-butoxy aluminumhydride in tetrahydrofuran to afford 2-( 8 '-acetoxyl,6-methanocyclodecapentaen-3 yl)propanol.

What is claimed is:

1. A compound selected from those represented by the following formulas(A) and (B):

R R2 R5 R1 R2 CZ a l wherein,

R is hydrogen, lower alkyl, lower monocyclic alkyl,

lower alkoxy or lower carboxylic acyloxy;

R is hydrogen or lower alkyl;

R is hydrogen, lower alkyl, methylene when taken together with R, orlower monocyclic alkyl when taken together with R and the carbon atom towhich R and R are attached;

R is COOR" in which R is hydrogen, lower alkyl or an alkali metal; and

is methylene, difluoromethylene.

2. A compound according to claim 1 wherein R is hydrogen and R is COOR3. A compound according to claim I wherein R is hydrogen, R is methyland R is COOR 4. A compound according to claim 1 wherein R is methoxyand R is COOR 5. A compound according to claim 1 wherein R is methoxy, Ris methyl and R is COOR.

6. A compound according to formula A of claim 1 wherein R is hydrogen, Xis methylene, R is methyl and R is COOR in which R is hydrogen.

7. A compound according to formula A of claim 1 wherein R is hydrogen, Xis difluoromethylene, R is methyl and R is COOR in which R is hydrogen.

8. A compound according to formula A of claim 1 wherein R is methoxy, Xis methylene, R is methyl and R is COOR", in which R is hydrogen.

9. A compound according to formula A of claim 1 wherein R is methoxy, Xis difluoromethylene, R is methyl and R is COOR-", in which R ishydrogen.

10. A compound according to formula A of claim 1 wherein R is methoxy, Xis dichloromethylene, R is methyl and R is COOR in which R is hydrogen.

11. A compound according to formula A of claim 1 wherein R is methoxy, Xis methylene, R is methyl, R is hydrogen, and R is -COOR, in which R ishydrogen or methyl.

X dichloromethylene or I n A .0

2. A compound according to claim 1 wherein R is hydrogen and R3 is -COOR5.
 3. A compound according to claim 1 wherein R is hydrogen, R1 is methyl and R3 is -COOR5.
 4. A compound according to claim 1 wherein R is methoxy and R3 is -COOR5.
 5. A compound according to claim 1 wherein R is methoxy, R1 is methyl and R3 is -COOR5.
 6. A compound according to formula A of claim 1 wherein R is hydrogen, X is methylene, R1 is methyl and R3 is -COOR5, in which R5 is hydrogen.
 7. A compound according to formula A of claim 1 wherein R is hydrogen, X is difluoromethylene, R1 is methyl and R3 is -COOR5, in which R5 is hydrogen.
 8. A compound according to formula A of claim 1 wherein R is methoxy, X is methylene, R1 is methyl and R3 is -COOR5, in which R5 is hydrogen.
 9. A compound according to formula A of claim 1 wherein R is methoxy, X is difluoromethylene, R1 is methyl and R3 is -COOR5, in which R5 is hydrogen.
 10. A compound according to formula A of claim 1 wherein R is methoxy, X is dichloromethylene, R1 is methyl and R3 is -COOR5, in which R5 is hydrogen.
 11. A compound according to formula A of claim 1 wherein R is methoxy, X is methylene, R1 is methyl, R2 is hydrogen, and R3 is -COOR5, in which R5 is hydrogen or methyl. 